Microtubules constitute spindles formed during cell division. Since tumor cells are in active cell division, agents inhibiting cell division are effective as anticancer agents. For this reason, anticancer agents targeting microtubules as the main structure of spindles or tubulin as a constituent protein thereof have been classically developed and used in treatment regardless of solid tumor or hematological tumor.
In fact, many compounds, such as vincristine and paclitaxel, which target microtubules, are widely used as anticancer agents. These agents are considered to exert their anticancer effects as a result of inhibiting spindle formation in tumor cells and thereby suppressing cell division.
These compounds, however, are known to cause serious adverse reactions such as peripheral neuropathy, because they target not only microtubules in spindles but microtubules in normal cells (e.g., Patent Literature 1 and Non Patent Literature 1). Also, particular isoforms of tubulin have been reported to have resistance to anticancer agents. It has been therefore required to develop a novel drug selectively targeting microtubules in tumor cells (Non Patent Literature 2).
In search for a compound selectively targeting microtubules in tumor cells, the present inventors have conducted analysis by focusing on TACC3, which are reportedly involved in microtubular polymerization and abnormally expressed in various tumors.
A gene encoding the TACC3 (transforming acidic coiled-coil 3) protein is considered to be a so-called cancer gene (e.g., Non Patent Literatures 3 to 8 and Patent Literature 2). TACC3 is also known to participate in spindle formation or the control of a mitotic apparatus involved in chromosome partitioning and cell division (e.g., Non Patent Literature 9). In addition, TACC3 and TOGp (tumor over-expressed gene) known to interact with TACC3 are overexpressed in various cancers.
The suppression of TACC3 expression induces different phenomena depending on the cell line used. For example, reduction in microtubular polymerization (Non Patent Literature 10) and apoptosis induced by chromosomal imbalance (Non Patent Literature 9) are reportedly observed.
These phenomena are explained, on the basis of findings obtained in Xenopus or Drosophila, by models in which TACC3 binds to TOGp and stabilizes microtubular polymerization in centrosomes during mitosis, thereby controlling cell division (Non Patent Literature 11).
The present inventors have experimented the suppression of TACC3 expression using TACC3-conditional knockout mice. As a result, the present inventors have found that lymphoma undergoes regression due to apoptosis, whereas normal thymus cells are found to express TACC3, but are not evidently affected thereby (Non Patent Literature 12). Thus, the present inventors have considered that compounds targeting at TACC3 may serve as excellent anticancer agents selectively acting on tumor cells, and already disclosed a method for screening for an anticancer agent targeting at TACC3 (Patent Literature 3).